The proteolytic activity in inflammatory bowel disease: insight from gut microbiota.

Inflammatory bowel disease (IBD) is a chronic, recurrent inflammatory disease caused by the destruction of the intestinal mucosal epithelium that affects a growing number of people worldwide. Although the etiology of IBD is complex and still elucidated, the role of dysbiosis and dysregulated proteolysis is well recognized. Various studies observed altered composition and diversity of gut microbiota, as well as increased proteolytic activity (PA) in serum, plasma, colonic mucosa, and fecal supernatant of IBD compared to healthy individuals. The imbalance of intestinal microecology and intestinal protein hydrolysis were gradually considered to be closely related to IBD. Notably, the pivotal role of intestinal microbiota in maintaining proteolytic balance received increasing attention. In summary, we have speculated a mesmerizing story, regarding the hidden role of PA and microbiota-derived PA hidden in IBD. Most importantly, we provided the diagnosis and therapeutic targets for IBD as well as the formulation of new treatment strategies for other digestive diseases and protease-related diseases.

Flavonoids From the Aerial Parts of Sophora tonkinensis and Their Potential Anti-Inflammatory Activities.

Four undescribed prenylated flavonoids, sophoratones A-D (1-4), and 17 known flavonoids, were obtained from the aerial parts of Sophora tonkinensis. Their structures with absolute configurations were elucidated by detailed interpretation of NMR spectroscopy, mass spectrometry, and ECD calculations. Meanwhile, the ability of these compounds to inhibit the release of nitric oxide (NO) by a lipopolysaccharide induced mouse in RAW 264.7 cells was assayed. The results indicated that some compounds exhibited clear inhibitory effects, with IC50 ranging from 19.91±1.08 to 35.72±2.92 µM. These results suggest that prenylated flavonoids from the aerial parts of S. tonkinensis could potentially be used as a latent source of anti-inflammatory agents.

Rapid and Accurate Identification of Cell Phenotypes of Different Drug Mechanisms by Using Single-Cell Fluorescence Images Via Deep Learning.

Identification of a drug mechanism is vital for drug development. However, it often resorts to the expensive and cumbersome omics methods along with complex data analysis. Herein, we developed a methodology to analyze organelle staining images of single cells using a deep learning algorithm (TL-ResNet50) for rapid and accurate identification of different drug mechanisms. Based on the organelle-related cell morphological changes caused by drug action, the constructed deep learning model can fast predict the drug mechanism with a high accuracy of 92%. Further analysis reveals that drug combination at different ratios can enhance a certain mechanism or generate a new mechanism. This work would highly facilitate clinical medication and drug screening.

Flavonoids from the Roots of Sophora flavescens and Their Potential Anti-Inflammatory and Antiproliferative Activities.

The phytochemical investigation of the roots of the traditional Chinese medicinal plant Sophora flavescens led to the isolation of two novel prenylflavonoids with an unusual cyclohexyl substituent instead of the common aromatic ring B, named 4',4'-dimethoxy-sophvein (17) and sophvein-4'-one (18), and 34 known compounds (1-16, 19-36). The structures of these chemical compounds were determined by spectroscopic techniques, including 1D-, 2D-NMR, and HRESIMS data. Furthermore, evaluations of nitric oxide (NO) production inhibitory activity against lipopolysaccharide (LPS)-treated RAW264.7 cells indicated that some compounds exhibited obvious inhibition effects, with IC50 ranged from 4.6 ± 1.1 to 14.4 ± 0.4 µM. Moreover, additional research demonstrated that some compounds inhibited the growth of HepG2 cells, with an IC50 ranging from 0.46 ± 0.1 to 48.6 ± 0.8 µM. These results suggest that flavonoid derivatives from the roots of S. flavescens can be used as a latent source of antiproliferative or anti-inflammatory agents.

Propagated α-synucleinopathy recapitulates REM sleep behaviour disorder followed by parkinsonian phenotypes in mice.

Idiopathic rapid eye movement sleep behaviour disorder (RBD) is now recognized as an early manifestation of α-synucleinopathies. Increasing experimental studies demonstrate that manipulative lesion or inactivation of the neurons within the sublaterodorsal tegmental nucleus (also known as the subcoeruleus nucleus in humans) can induce RBD-like behaviours in animals. As current RBD animal models are not established on the basis of α-synucleinopathy, they do not represent the pathological substrate of idiopathic RBD and thus cannot model the phenoconversion to Parkinson's disease. The purpose of this study was therefore to establish an α-synucleinopathy-based RBD animal model with the potential to convert to parkinsonian disorder. To this end, we first determined the functional neuroanatomical location of the sublaterodorsal tegmental nucleus in wild-type C57BL/6J mice and then validated its function by recapitulating RBD-like behaviours based on this determined nucleus. Next, we injected preformed α-synuclein fibrils into the sublaterodorsal tegmental nucleus and performed regular polysomnographic recordings and parkinsonian behavioural and histopathological studies in these mice. As a result, we recapitulated RBD-like behaviours in the mice and further showed that the α-synucleinopathy and neuron degeneration identified within the sublaterodorsal tegmental nucleus acted as the neuropathological substrates. Subsequent parkinsonian behavioural studies indicated that the α-synucleinopathy-based RBD mouse model were not stationary, but could further progress to display parkinsonian locomotor dysfunction, depression-like disorder, olfactory dysfunction and gastrointestinal dysmotility. Corresponding to that, we determined α-synuclein pathology in the substantia nigra pars compacta, olfactory bulb, enteral neuroplexus and dorsal motor nucleus of vagus nerve, which could underlie the parkinsonian manifestations in mice. In conclusion, we established a novel α-synucleinopathy-based RBD mouse model and further demonstrated the phenoconversion of RBD to Parkinson's disease in this animal model.

Deep Learning Promotes Profiling of Multiple miRNAs in Single Extracellular Vesicles for Cancer Diagnosis.

Extracellular vesicle microRNAs (EV miRNAs) are critical noninvasive biomarkers for early cancer diagnosis. However, accurate cancer diagnosis based on bulk analysis is hindered by the heterogeneity among EVs. Herein, we report an approach for profiling single-EV multi-miRNA signatures by combining total internal reflection fluorescence (TIRF) imaging with a deep learning (DL) algorithm for the first time. This innovative technique allows for the precise characterization of EV miRNAs at the single-vesicle level, overcoming the challenges posed by EV heterogeneity. TIRF with high resolution and a signal-to-noise ratio can simultaneously detect multi-miRNAs in situ in individual EVs. DL algorithm avoids complicated and inaccurate artificial feature extraction, achieving automated high-resolution image analysis. Using this approach, we reveal that the main variation of EVs from 5 cancer cells and normal plasma is the triple-positive EV subpopulation, and the classification accuracy of single triple-positive EVs from 6 sources can reach above 95%. In the clinical cohort, 20 patients (5 lung cancer, 5 breast cancer, 5 cervical cancer, and 5 colon cancer) and 5 healthy controls are predicted with an overall accuracy of 100%. This single-EV strategy provides new opportunities for exploring more specific EV biomarkers to achieve cancer diagnosis and classification.

Systemic lupus erythematosus presenting with progressive massive ascites and CA-125 elevation indicating Tjalma syndrome? A case report.

BACKGROUND: Ascites, pleural effusion and raised CA-125 in the absence of malignancy in systemic lupus erythematosus is known as Tjalma syndrome. CASE SUMMARY: We report a special case of a systemic lupus erythematosus patient presenting with Tjalma syndrome. She presented with ascites and elevated CA-125 in the absence of benign or malignant ovarian tumor and no pleural effusions, which is an unusual presentation for this rare condition. CONCLUSION: Tjalma syndrome can present with massive ascites alone without pleural or pericardial effusions.

[Clinical effects of arthroscopy-assisted anterior cruciate ligament tibial eminence avulsion fracture compared with traditional open surgery:a Meta-analysis].

OBJECTIVE: To systematically evaluate the clinical efficacy of arthroscopy and traditional incision in the treatment of tibial avulsion fracture of anterior cruciate ligament (ACL). METHODS: From July 2010 to July 2020, clinical comparative trial about arthroscopy and traditional incision in the treatment of ACL tibial avulsion fracture was conducted by using computer-based databases, including Embase, Pubmed, Central, Cinahl, PQDT, CNKI, Weipu, Wanfang, Cochrane Library, CBM. Literature screening and data extraction were carried out according to the inclusion and exclusion criteria, and the quality of the included literature was evaluated by improved Jadad score and Ottawa Newcastle scale (NOS). The operation time, hospital stay, fracture healing time, knee range of motion, postoperative excellent and good rate, complication rate, Lysholm score, International Knee Documentation Committee (IKDC) score and Tegner score were statistically analyzed by Review Manager 5.3 software. RESULTS: Finally, 16 literatures were included, including 1 randomized controlled trial and 15 non randomized controlled trials, with a total of 822 patients (405 in arthroscopy group and 417 in traditional incision group). Meta analysis showed that the operation time [MD=-9.03, 95% CI(-14.36, -3.70), P<0.001], hospital stay [MD=-5.81, 95%CI(-9.32, -2.31), P=0.001] and fracture healing time [MD=-14.61, 95% CI(-17.93, -11.28), P<0.001] in the arthroscopy group were better than those in the traditional incision group. The incidence of complications in arthroscopy group was lower than that in traditional incision group[OR=0.15, 95%CI(0.07, 0.33), P<0.001]. The postoperative excellent and good rate[OR=4.39, 95%CI (1.96, 9.82), P<0.001], knee mobility[MD=6.78, 95%CI(2.79, 10.77), P<0.001], Lysholm score[MD=11.63, 95%CI(4.91, 18.36), P<0.001], IKDC score[MD=7.83, 95%CI(6.09, 9.57), P<0.001] and Tegner score[MD=0.60, 95%CI(0.31, 0.89), P<0.001] in the arthroscopic group were higher than those in the traditional incision group. CONCLUSION: Compared with the traditional open reduction and internal fixation, arthroscopic surgery in patients with ACL tibial avulsion fracture can shorten the operation time, hospital stay and fracture healing time, reduce the incidence of postoperative complications, and obtain good postoperative knee function. It can be recommended as one of the first choice for patients with ACL tibial avulsion fracture.

Mesencephalic dopamine neurons are essential for modafinil-induced arousal.

BACKGROUND AND PURPOSE: Modafinil is a potent eugeroic (wakefulness-promoting) drug that is prescribed to treat narcolepsy and has a low incidence of abuse. Although previous studies have shown that modafinil-induced arousal depends on the dopamine receptors and transporters, the specific part/s of the dopamine transmitter system underlying this mechanism remained unclear. Here, we investigated the role of mesencephalic dopamine neurons in modafinil-evoked arousal. EXPERIMENTAL APPROACH: A dopamine indicator (dLight1.1) was employed to detect dopamine changes in the nucleus accumbens (NAc) and dorsal striatum. We specifically lesioned mesencephalic dopamine neurons via diphtheria toxin (DTA) in the dopamine transporter (DAT)-Cre mice. Then, the sleep-wake states were recorded to evaluate the effect of modafinil on arousal. Finally, the extent of DTA-induced lesions was determined by immunohistochemistry. KEY RESULTS: Modafinil promptly increased dopamine levels in the NAc and dorsal striatum in a dose-dependent manner. Lesioning of dopamine neurons in the substantia nigra pars compacta (SNc) or ventral tegmental area (VTA) had no significant effects on physiological sleep-wake cycles. Modafinil at 90 mg·kg-1 increased continuous wakefulness for 355 min in control mice. However, these effects were slightly decreased by 6.7% in the SNc-lesioned mice and were prominently diminished by 32.8% in VTA-lesioned mice. Furthermore, the modafinil-induced arousal was completely blocked in the SNc-VTA-lesioned mice, whereas lesions of the dorsal raphé nucleus had no effect. CONCLUSION AND IMPLICATIONS: Taken together, our findings indicate that mesencephalic dopamine neurons are essential for modafinil-induced arousal.

Studies of Articular Cartilage Repair from 2009 to 2018: A Bibliometric Analysis of Articles.

OBJECTIVE: To perform a bibliometric analysis of research on articular cartilage repair published in Chinese and English over the past decade. Fundamental and clinical research topics of high interest were further comparatively analyzed. METHODS: Relevant studies published from 1 January 2009 to 31 December 2018 (10 years) were retrieved from the Wanfang database (Chinese articles) and six databases, including MEDLINE, WOS, INSPEC, SCIELO, KJD, and RSCI on the website "Web of Science" (English articles), using key words: "articular cartilage" AND "injury" AND "repair". The articles were categorized according to research focuses for a comparative analysis between those published in Chinese vs English, and further grouped according to publication date (before and after 2014). A comparative analysis was performed on research focus to characterize the variation in research trends between two 5-year time spans. Moreover, articles were classified as basic and clinical research studies. RESULTS: Overall, 5762 articles were retrieved, including 2748 in domestic Chinese journals and 3014 in international English journals. A total of 4937 articles focused on the top 10 research topics, with the top 3 being stem cells (32.1%), tissue-engineered scaffold (22.8%), and molecular mechanisms (16.4%). Differences between the numbers of Chinese and English papers were observed for 3 topics: chondrocyte implantation (104 vs 316), osteochondral allograft (27 vs 86), and microfracture (127 vs 293). The following topics gained more research interest in the second 5-year time span compared with the first: microfracture, osteochondral allograft, osteochondral autograft, stem cells, and tissue-engineered scaffold. Articles with a focus on three-dimensional-printing technology have shown the fastest increase in publication numbers. Among 5613 research articles, basic research studies accounted for the majority (4429), with clinical studies described in only 1184 articles. The top 7 research topics of clinical studies were: chondrocyte implantation (28.7%), stem cells (21.9%), microfracture (19.2%), tissue scaffold (10.6%), osteochondral autograft (10.5%), osteochondral allograft (6.3%), and periosteal transplantation (2.8%). CONCLUSION: Studies focused on stem cells and tissue-engineered scaffolds led the field of damaged articular cartilage repair. International researchers studied allograft-related implantation approaches more often than Chinese researchers. Traditional surgical techniques, such as microfracture and osteochondral transplantation, gained high research interest over the past decade.

Dorsal Striatum Dopamine Levels Fluctuate Across the Sleep-Wake Cycle and Respond to Salient Stimuli in Mice.

Dopamine is involved in numerous neurological processes, and its deficiency has been implicated in Parkinson's disease, whose patients suffer from severe sleep disorders. Destruction of nigrostriatal dopaminergic neurons or dorsal striatum disrupts the sleep-wake cycle. However, whether striatal dopamine levels correlate with vigilance states still remains to be elucidated. Here, we employed an intensity-based genetically encoded dopamine indicator, dLight1.1, to track striatal dopamine levels across the spontaneous sleep-wake cycle and the dopaminergic response to external stimuli. We found that the striatal dLight1.1 signal was at its highest during wakefulness, lower during non-rapid eye movement (non-REM or NREM) sleep, and lowest during REM sleep. Moreover, the striatal dLight1.1 signal increased significantly during NREM sleep-to-wake transitions, while it decreased during wake-to-NREM sleep transitions. Furthermore, different external stimuli, such as sudden door-opening of the home cage or cage-change to a new environment, caused striatal dopamine release, whereas an unexpected auditory tone did not. Finally, despite both modafinil and caffeine being wake-promoting agents that increased wakefulness, modafinil increased striatal dopamine levels while caffeine did not. Taken together, our findings demonstrated that striatal dopamine levels correlated with the spontaneous sleep-wake cycle and responded to specific external stimuli as well as the stimulant modafinil.

Two diammonium copper azides with similar layerlike magnetic substructures made of chains of serially connected Cu6 rings show cation-modulated magnetism.

We present here the first examples of Cu-azide compounds synthesized by using protonated diamine ions as cationic templates: (dmenH(2))[Cu(6)(N(3))(14)] and (trimenH(2))[Cu(6)(N(3))(14)](dmenH(2)(2+): N,N'-dimethylethylenediammonium; trimenH(2)(2+): N,N,N'-trimethylethylenediammonium). Both compounds possess a similar, rarely observed anionic Cu-azide layer, which consists of [Cu(6)(N(3))(14)(2-)](n) anionic chains linked by asymmetric end-to-end azido bridges. The chain, in turn, is made up of elongated Cu(6) rings, with double and single end-on azido linkages between the square-planar Cu(2+) sites within the ring and double end-on azido bridges serially connecting the rings. The molecular geometry results in ferromagnetic interactions within the Cu-azide layer in both compounds. The interlayer separations are determined by the cations, with the shortest interlayer CuCu separations being 8.016 A for the dmenH(2)(2+) compound and 9.106 A for the trimenH(2)(2+) compound. These different interlayer separations tune the magnetic properties of the two materials. The dmenH(2)(2+) compound displays long-range antiferromagnetic ordering at low temperature and short-range ferromagnetic interaction at high temperature, while only short-range ferromagnetism was observed in the trimenH(2)(2+) compound at 2-300 K.